N-acyl-n{40 -(halogenated aryl ureas as antibacterial agents)

ABSTRACT

The use of N-Acyl-N&#39;&#39;-(halogenated aryl) ureas as antibacterial agents and germicidal detergent compositions containing such ureas are disclosed.

United States Patent Taber et al.

[54] N-ACYL-N '-(HALOGENATED ARYL UREAS AS ANTIBACTERIAL AGENTS) [72]Inventors: David Taber, Evanston; Moneeb H.

Zakaria, Chicago, both of III.

[73] Assignee: Armour and Company, Chicago, Ill.

[22] Filed: Oct. 23, 1969 [21 Appl. No.: 868,937

Related US. Application Data [62] Division of Ser. No. 638,585, May 15,I967,

abandoned.

[52] US. Cl. ..424/322, 252/ 106, 252/107 [5 I] Int. Cl. ..A0ln 9/20[58] Field of Search ..260/553 G, 552; 424/322;

[ 51 Aug. 22, 1972 Speziule et al., .I. Of Organic Chemistry, Vol. 28,N0. 7, pages 1805- l8ll (1963) Primary Examiner-Albert T. MeyersAssistant ExaminerVincent D. Turner Att0rneyCarl C. Batz and Richard G.Harrer [57] ABSTRACT The use of N-AcyI-N'-(halogenated aryl) ureas asantibacterial agents and germicidal detergent compositions containingsuch ureas are disclosed.

2 Claims, No Drawings N-ACYL-N-(HALOGENATED ARYL UREAS AS ANTIBACTERIALAGENTS) This is a division of application Ser. No. 638,585, filed May15, 1967, and now abandoned.

This invention relates to new antibacterial agents and more particularlyto new germicidal detergent compositions.

The popularity of detergent compositions, for both laundry and toiletuse, containing germicidal agents has increased tremendously over thepast few years. It is estimated that more than 20 percent of the toiletbar soap sales are now of products containing a germicidal agent; andthis percentage is steadily increasing. Heretofore many compounds havebeen investigated as possible detergent germicides. While numeroussubstances indicate a degree of antibacterial activity, few produce thedesired results necessary for use as effective detergent gerrnicides. Inmany cases the gennicide is either incompatible with the detergent orelse getmicidal activity is abated when the germicide is incorporatedinto the detergent. Further, certain detergent products, such as toiletsoap, have the added requirement that the gerrnicide used must not beharmful to the human skin. Thus, it is desirable that a considerablevariety of germicides be made available, from which a selection may bemade for use in various detergent media.

One aspect of the present invention lies in the discovery that certainacyl ureas have definite antibacterial properties and that theseproperties are maintained in the presence of an alkaline agent such assoap or other detergent compositions. These compounds are, to the bestof our knowledge, not harmful to human skin.

Therefore, it is an object of this invention to provide newantibacterial agents which are compatible with detergent compositionsand which maintain this activity even when incorporated into detergentcompositions. Other objects and advantages, and a further understandingof this invention, will appear in the ensuing description and examples.

In one specific embodiment, our invention may be exemplified by anantiseptic detergent composition comprising a detergent and agermicidally eflective amount of an N-acylN-(halogenated aryl) ureacompound of the structure:

O O Xn wherein R is a radical selected from the group consisting ofaliphatic radicals containing from two to 13 carbon atoms andhalogenated phenyl radicals, X is halogen such as chlorine, bromine,fluorine, trichloromethyl, trifluoromethyl and the like, and n isaninteger from 1 to 5.

N-acyl ureas of the above structure may be prepared generally byreacting either aliphatic amides (R- CONI-l,) or halogenated benzamides(X,,A, CONl-l with a halogenated aryl aryl isocyanate, such as 3,4-dichlorophenyl isocyanate, in an inert solvent under anhydrousconditions and at reflux temperatures. The above reaction may beillustrated by the following chemical equation using the3,4-dichlorophenyl isocyanate reactant:

O iN @C.

substitutions on our acyl ureas may be varied. Suitable halogenatedradicals include chlorobenzyls, bromobenzyls, fluorobenzyls,chloromethylphenyls, dichloromethylphenyls, trichloromethylphenyls,trifluoromethylphenyls, chloronapthyls,

bromonapthyls, fluoronaphthyls, and the like.

Relatively small amounts of the N-acyl ureas are sufficient to make thedetergent composition antiseptic. The amount to be used in particularinstance will vary over a wide range depending upon such factors as thedegree of eflectiveness desired, the particular N-acyl urea employed,and cost. Generally, from 0.2 percent to about 5 percent based on theweight of the detergent will provide desirable antisepsis. It should beunderstood that lesser or greater amounts are operable but withoutsubstantial advantages. A preferred range is an amount in the order offrom about 0.5 percent to about 3 percent, based on the final weight ofthe detergent composition.

In order to more fully describe the nature of the novel compositions ofthe present invention and the manner in which they may be used, thefollowing illustrative specific examples are provided.

EXAMPLE I l-(2,4-Dichlorobenzoyl)-3-( 3,4-dichlorophenyl) urea To a 200ml. round bottom flask fitted with a condenser and a drying tube througha Dean-Stark trap, was added 10.0 grams (0.052 mole) of 2,4-dichlorobenzamide in 50 rnl..of benzene. The mixture was heated toreflux and any moisture present was removed by azeotropic distillationwith benzene. 3,4- Dichlorophenyl isocyanate (12.0 grams, 0.063 mole) inml. .of o-dichlorobenzene was then added. The temperature was raisedsufficiently to cause the solvent to reflux and benzene was drawn offthrough the Dean- Stark trap. The mixture was then heated under refluxfor a total of 12 hours, and gradually cooled to room temperature. Awhite precipitate was obtained, which was filtered off, air dried andweighed. There was ob tained 12 grams (61 percent yield) of 1(2,4-dichlorobenzoyl)-3-(3,4-dichlorophenyl) urea, (melting point of 222225C.). The reaction product was recrystallized from acetone to give apure, white crystalline product (melting point of 222 C.) having theformula:

EXAMPLE 11 Preparation of N-acylN' 3,4-dichlorophenyl) ureas In similarprocedure as set forth in Example I, other acyl ureas were prepared.Since 3,4-dichlorophenyl isocyanate readily forms 3,3,4,4-tetrachlorocarbanilide in the presence of water, it is essentialthat water be excluded from the reaction. One method to accomplish thisis by first heating the amide in benzene and azeotroping any waterpresent. Then, an equimolar amount, plus some excess, of3,4-dich1orophenyl isocyanate together with o-dichlorobenzene solventare added and the mixture is heated to a higher temperature, at whichthe benzene is taken off. The mixture is then reacted for about 10 hoursunder reflux. At the end of this period most of the solvent is distilledE and the residue is triturated with benzene or another suitablesolvent, filtered, and air dried. In most cases, this residue will befound to contain a small amount of 3,3,4,4-tetrachloracarbanilidetogether with the desired acyl urea. By boiling the residue in benzene,e n w ile. hqtiand Cooling the fil ra e heN- y urea is precipitated. Itmay then be separated and air dried. The formation of 3,3,4,4'-tetrachlorocarbanilide may also be avoided by carrying out thereaction in dry toluene. By this method, equimolar amounts of 3,4-

-dich1orophenyl isocyanate and the desired amide reactant may be addedto dry toluene and the reaction maintained under reflux. The toluene isthen removed, as by distillation, and the residue is either filtereddirectly or triturated with petroleum ether and then filtered. Thereaction product may then be recrystallized from alcohol or othersolvents such as benzene.

In order to be sure that the reaction product was free of3,3,4,4'-tetrachlorcarbanilide when the product was triturated withbenzene, the reaction product was boiled in benzene, filtered while hot,and cooled, whereupon the acyl urea precipitated and was separated andair dried. Where the reaction was run in dry toluene, the product waseither recrystallized from alcohol or benzene. The acyl ureas obtainedare set forth in Table I. In Table I, the compounds are listed bysetting forth only the R portion of the general formula Also, the meansby which the removal of 3,3',4,4'- tetrachlorocarbanilide is effected isset forth in the table.

TABLE I n-C H, 128-9 82 54.2 54.32 6.02 6.38

n-C H 114-5 78 56.4 56.44 6.39 6.04

n-C I-i 105-6 70 59.0 58.87 7.25 7.01

cenyl 100 69 57.89 6:45 6.34 Recrystallized from alcohol Recrystallizedfrom alcohol Triturate with acetone n-C H 99-1062 60.8 60.76 7.71. 7.63

nicotinyl 272-3 94 50.4 50.47 2.90 2.79

o-chlorophenyl 208 70 49.2 49.51 2.63 2.05 Recrystallized from acetonep-chlorophenyl 273 2.90 Triturate with acetone 2,4-dichlorophenyl 222 6544.5 45.02 2.12 Recrystallized from acetone 3,4-dichlorophenyl 235-6 9644.5 44.79 2.30 RccrystuL lized from acetone EXAMPLE III Germicidalactivity of the acyl ureas prepared in the above examples was determinedas follows:

The various individual acyl ureas were dissolved in dimethylformamide ata 1.0 percent level. Suspensions in a 10 percent soap solution were thenprepared. The soap utilized was neutral white toilet soap containingabout 20 percent by weight of sodium coco soap and about percent byweight of sodium tallow soap. The

concentration of acyl urea in the soap solution was 1,000 ppm, or 0.1percent. Thereafter, serial dilutions were made containing 100 ppm and10 ppm respectively of the acyl urea.

Varying amounts of the soap solutions containing the acyl ureas werethoroughly dispersed into measured amounts of sterile liquid nutrientagar so as to obtain concentrations of the acyl urea ranging from 0.05to 20 ppm. Plates were then poured, allowed to solidify, and streakedwith a standard 4 mm. loopful of a 24-hour broth culture ofStaphylococcus aureus FDA 209. After incubation for 24 hours at 37 C.,the bacteriostatic endpoint was determined. The bacteriostatic endpoint,hereinafter called the minimum inhibitory concentration, represents theminimum concentration in ppm of the bacteriostatic agent necessary tocompletely inhibit all growth of S. aureus.

Table II givesthe endpoints or the minimum inhibitory concentration ofthe 10 percent soap solution, without germicide added and with theaddition of the N-acyl-N-(3,4-dichlorophenyl) ureas prepared in ExamplesI and 11.

The results obtained above with respect to bacteriostatic activity inthe specific soap mentioned above (20/80 sodium coco/tallow) areobtained with soaps generally. The activity exhibited by these compoundsis independent of the soap vehicle, and other media may be used such .asanionic and non-ionic type synthetic detergents. At the same time, soapis a system in which the compounds are highly effective. Soap refers tothe water-soluble metallic, ammonium, or organic base salts of variousfatty acids, such as lard, lauric, oleic, myristic, palrnitic, steraicand the like.

While this invention has been described with respect to certainembodiments, it is not so limited; and it is to be understood thatvariations and modifications thereof, obvious to those skilled in theart, may be 5 made without departing from the spirit of scope of ourinvention.

What is claimed is:

l. A process for inhibiting the growth of bacteria which comprisescontacting said bacteria with a bacter- 10 icidally effective amount ofan N-acyl-N'-(halogenated aryl) urea of the structure:

l l li l'I wherein R is selected from the group consisting of aliphaticradicals containing from two to 13 carbon atoms und ,X is selected fromthe group consisting of chlorine, bromine, fluorine, trichloromethyl,and trifluoromethyl; and n is an integer from 1 to 5.

2. The process of claim 1 in which said urea is l-(2,4-

dichlorobenzoyl)-3 -(3,4-dichlorophenyl) urea.

2. The process of claim 1 in which said urea is1-(2,4-dichlorobenzoyl)-3-(3,4-dichlorophenyl) urea.